Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle

ABSTRACT Epstein-Barr virus (EBV) is a human herpesvirus that is associated with lymphomas as well as nasopharyngeal and gastric carcinomas. Although carcinomas account for almost 90% of EBV-associated cancers, progress in examining EBV’s role in their pathogenesis has been limited by difficulty in...

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Autores principales:	Mark R. Eichelberg, Rene Welch, J. Tod Guidry, Ahmed Ali, Makoto Ohashi, Kathleen R. Makielski, Kyle McChesney, Nicholas Van Sciver, Paul F. Lambert, Sündüz Keleș, Shannon C. Kenney, Rona S. Scott, Eric Johannsen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	EBV NPC differentiation gastric cancer oral keratinocytes Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/23bfdf5ee4d64f5eb94ddf1bfd5f97d5
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spelling	oai:doaj.org-article:23bfdf5ee4d64f5eb94ddf1bfd5f97d52021-11-15T16:22:11ZEpstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle10.1128/mBio.01332-192150-7511https://doaj.org/article/23bfdf5ee4d64f5eb94ddf1bfd5f97d52019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01332-19https://doaj.org/toc/2150-7511ABSTRACT Epstein-Barr virus (EBV) is a human herpesvirus that is associated with lymphomas as well as nasopharyngeal and gastric carcinomas. Although carcinomas account for almost 90% of EBV-associated cancers, progress in examining EBV’s role in their pathogenesis has been limited by difficulty in establishing latent infection in nontransformed epithelial cells. Recently, EBV infection of human telomerase reverse transcriptase (hTERT)-immortalized normal oral keratinocytes (NOKs) has emerged as a model that recapitulates aspects of EBV infection in vivo, such as differentiation-associated viral replication. Using uninfected NOKs and NOKs infected with the Akata strain of EBV (NOKs-Akata), we examined changes in gene expression due to EBV infection and differentiation. Latent EBV infection produced very few significant gene expression changes in undifferentiated NOKs but significantly reduced the extent of differentiation-induced gene expression changes. Gene set enrichment analysis revealed that differentiation-induced downregulation of the cell cycle and metabolism pathways was markedly attenuated in NOKs-Akata relative to that in uninfected NOKs. We also observed that pathways induced by differentiation were less upregulated in NOKs-Akata. We observed decreased differentiation markers and increased suprabasal MCM7 expression in NOKs-Akata versus NOKs when both were grown in raft cultures, consistent with our transcriptome sequencing (RNA-seq) results. These effects were also observed in NOKs infected with a replication-defective EBV mutant (AkataΔRZ), implicating mechanisms other than lytic-gene-induced host shutoff. Our results help to define the mechanisms by which EBV infection alters keratinocyte differentiation and provide a basis for understanding the role of EBV in epithelial cancers. IMPORTANCE Latent infection by Epstein-Barr virus (EBV) is an early event in the development of EBV-associated carcinomas. In oral epithelial tissues, EBV establishes a lytic infection of differentiated epithelial cells to facilitate the spread of the virus to new hosts. Because of limitations in existing model systems, the effects of latent EBV infection on undifferentiated and differentiating epithelial cells are poorly understood. Here, we characterize latent infection of an hTERT-immortalized oral epithelial cell line (NOKs). We find that although EBV expresses a latency pattern similar to that seen in EBV-associated carcinomas, infection of undifferentiated NOKs results in differential expression of a small number of host genes. In differentiating NOKs, however, EBV has a more substantial effect, reducing the extent of differentiation and delaying the exit from the cell cycle. This effect may synergize with preexisting cellular abnormalities to prevent exit from the cell cycle, representing a critical step in the development of cancer.Mark R. EichelbergRene WelchJ. Tod GuidryAhmed AliMakoto OhashiKathleen R. MakielskiKyle McChesneyNicholas Van SciverPaul F. LambertSündüz KeleșShannon C. KenneyRona S. ScottEric JohannsenAmerican Society for MicrobiologyarticleEBVNPCdifferentiationgastric canceroral keratinocytesMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	EBV NPC differentiation gastric cancer oral keratinocytes Microbiology QR1-502
spellingShingle	EBV NPC differentiation gastric cancer oral keratinocytes Microbiology QR1-502 Mark R. Eichelberg Rene Welch J. Tod Guidry Ahmed Ali Makoto Ohashi Kathleen R. Makielski Kyle McChesney Nicholas Van Sciver Paul F. Lambert Sündüz Keleș Shannon C. Kenney Rona S. Scott Eric Johannsen Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle
description	ABSTRACT Epstein-Barr virus (EBV) is a human herpesvirus that is associated with lymphomas as well as nasopharyngeal and gastric carcinomas. Although carcinomas account for almost 90% of EBV-associated cancers, progress in examining EBV’s role in their pathogenesis has been limited by difficulty in establishing latent infection in nontransformed epithelial cells. Recently, EBV infection of human telomerase reverse transcriptase (hTERT)-immortalized normal oral keratinocytes (NOKs) has emerged as a model that recapitulates aspects of EBV infection in vivo, such as differentiation-associated viral replication. Using uninfected NOKs and NOKs infected with the Akata strain of EBV (NOKs-Akata), we examined changes in gene expression due to EBV infection and differentiation. Latent EBV infection produced very few significant gene expression changes in undifferentiated NOKs but significantly reduced the extent of differentiation-induced gene expression changes. Gene set enrichment analysis revealed that differentiation-induced downregulation of the cell cycle and metabolism pathways was markedly attenuated in NOKs-Akata relative to that in uninfected NOKs. We also observed that pathways induced by differentiation were less upregulated in NOKs-Akata. We observed decreased differentiation markers and increased suprabasal MCM7 expression in NOKs-Akata versus NOKs when both were grown in raft cultures, consistent with our transcriptome sequencing (RNA-seq) results. These effects were also observed in NOKs infected with a replication-defective EBV mutant (AkataΔRZ), implicating mechanisms other than lytic-gene-induced host shutoff. Our results help to define the mechanisms by which EBV infection alters keratinocyte differentiation and provide a basis for understanding the role of EBV in epithelial cancers. IMPORTANCE Latent infection by Epstein-Barr virus (EBV) is an early event in the development of EBV-associated carcinomas. In oral epithelial tissues, EBV establishes a lytic infection of differentiated epithelial cells to facilitate the spread of the virus to new hosts. Because of limitations in existing model systems, the effects of latent EBV infection on undifferentiated and differentiating epithelial cells are poorly understood. Here, we characterize latent infection of an hTERT-immortalized oral epithelial cell line (NOKs). We find that although EBV expresses a latency pattern similar to that seen in EBV-associated carcinomas, infection of undifferentiated NOKs results in differential expression of a small number of host genes. In differentiating NOKs, however, EBV has a more substantial effect, reducing the extent of differentiation and delaying the exit from the cell cycle. This effect may synergize with preexisting cellular abnormalities to prevent exit from the cell cycle, representing a critical step in the development of cancer.
format	article
author	Mark R. Eichelberg Rene Welch J. Tod Guidry Ahmed Ali Makoto Ohashi Kathleen R. Makielski Kyle McChesney Nicholas Van Sciver Paul F. Lambert Sündüz Keleș Shannon C. Kenney Rona S. Scott Eric Johannsen
author_facet	Mark R. Eichelberg Rene Welch J. Tod Guidry Ahmed Ali Makoto Ohashi Kathleen R. Makielski Kyle McChesney Nicholas Van Sciver Paul F. Lambert Sündüz Keleș Shannon C. Kenney Rona S. Scott Eric Johannsen
author_sort	Mark R. Eichelberg
title	Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle
title_short	Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle
title_full	Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle
title_fullStr	Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle
title_full_unstemmed	Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle
title_sort	epstein-barr virus infection promotes epithelial cell growth by attenuating differentiation-dependent exit from the cell cycle
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/23bfdf5ee4d64f5eb94ddf1bfd5f97d5
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Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle

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